Methods for treating heartburn and/or preventing gastric bleeding or hemorrhage in patients receiving clopidogrel therapy

ABSTRACT

The present invention relates to methods of treating heartburn in a patient receiving clopidogrel therapy. In another aspect, the present invention relates to methods of preventing gastric bleeding or hemorrhage in patients receiving clopidogrel therapy.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This is a continuation of U.S. patent application Ser. No. 13/411,701,filed on Mar. 5, 2012, which claims priority to U.S. Provisional PatentApplication No. 61/467,545, filed on Mar. 25, 2011, the entire contentsof all of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods of treating heartburn in apatient receiving clopidogrel therapy. In another aspect, the presentinvention relates to methods of preventing gastric bleeding orhemorrhage in patients receiving clopidogrel therapy.

BACKGROUND

Clopidogrel bisulfate (currently sold under the brand name Plavix;clopidogrel bisulfate will occasionally be referred to herein simply as“clopidogrel”) is a thienopyridine class inhibitor of P2Y₁₂ ADP plateletreceptors. Chemically, it is referred to as methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1) and is a prodrug. Clopidogrel is available asa 75 mg or 300 mg tablet.

Clopidogrel is an antiplatelet agent used to inhibit blood clots incoronary artery disease, peripheral vascular disease and cerebrovasculardisease. Specifically, clopidogrel is indicated for acute coronarysyndrome (“ACS”): (1) for patients with non-ST-segment elevation ACS;(2) for patients with ST-elevation myocardial infarction; and (3) recentmyocardial infarction, recent stroke, or established peripheral arterialdisease. Clopidogrel is also used, along with aspirin, for theprevention of thrombosis after placement of intracoronary stent or as analternative antiplatelet drug for patients who are intolerant toaspirin.

Proton pump inhibitors (PPIs) are a group of drugs whose main action isa pronounced and long-lasting reduction of gastric acid production. ManyPPIs are benzimidazole derivatives (specifically, substitutedbenzimidazole derivatives). Examples of some of the most common PPIsinclude:

Omeprazole (currently sold under the brand names: Losec, Prilosec,Zegerid, Lomac, Omepral, Omez);

Lansoprazole (currently sold under the brand names: Prevacid, Zoton,Inhibitol, Levant, Lupizole);

Dexlansoprazole (currently sold under the brand name: Dexilant);

Esomeprazole (currently sold under the brand names: Nexium, Esotrex);and

Pantoprazole (currently sold under the brand names: Protonix, Somac,Pantoloc, Pantozol, Zurcal, Zentro, Pan)

The PPIs in the above list are substituted benzimidazoles that suppressgastric acid secretion by specific inhibition of the H⁺/K⁺ ATPase enzymesystem of the secretory surface of the gastric parietal cell.

Proton pump inhibitors are often prescribed with clopidogrel to reducethe risk of gastric bleeding or hemorrhage associated with theanti-platelet effect of clopidogrel therapy. There is significantongoing concern regarding the clinical outcomes of patients takingclopidogrel and PPIs. Recently published studies suggested that PPIshave the potential to reduce the clopidogrel, G-protein coupled, 12(P2Y12) adenosine diphosphate (ADP) receptor (Gilard M, Arnaud B,Cornily J C, Le Gal G, Lacut K, Le Calvez G, et al. Influence ofomeprazole on the antiplatelet action of clopidogrel associated withaspirin: the randomized, double-blind OCLA (Omeprazole ClopidogrelAspirin) study. J Am Coll Cardiol 2008; 51(3):256-60; Pezalla E, Day D,Pulliadath I. Initial assessment of clinical impact of a druginteraction between clopidogrel and proton pump inhibitors. J Am CollCardiol 2008; 52(12): 1038-39; Ho P, Maddox T, Wang L, Fihn S, Jesse R,Peterson E, et al. Proton pump inhibitors may attentuate the benefits ofclopidogrel among ACS patients: empirical evidence from 3,311 ACSpatients. Circulation 2008; 118:S_1165. Abstract No. 6241; Aubert R,Epstein R, Teagarden J, Xia F, Yao J, Desta Z, et al. Proton pumpinhibitors effect on clopidogrel effectiveness: the clopidogrel Medcooutcomes study. Circulation 2008; 118:S_815. Abstract 3998).

Clopidogrel itself does not possess antiplatelet aggregation activity,but requires metabolism by hepatic cytochrome P450s, including CYP2C19,to an active metabolite that then blocks platelet P2Y12 receptors.Because PPIs are known inhibitors of CYP2C19, a plausible explanationfor this reduced effectiveness of clopidogrel may be a metabolism-baseddrug-drug interaction (DDI) whereby the PPI inhibits the conversion ofclopidogrel to its active metabolite by inhibiting CYP2C19. The FDA hasmade warnings about clinically relevant DDI with respect to clopidogreland certain PPIs. For example, on Nov. 17, 2009, the FDA posted thefollowing warning about a drug interaction between clopidogrel andomeprazole:

-   -   “FDA notified healthcare professionals of new safety information        concerning an interaction between clopidogrel (Plavix), an        anti-clotting medication, and omeprazole (Prilosec/Prilosec        OTC), a proton pump inhibitor (PPI) used to reduce stomach acid.        New data show that when clopidogrel and omeprazole are taken        together, the effectiveness of clopidogrel is reduced. Patients        at risk for heart attacks or strokes who use clopidogrel to        prevent blood clots will not get the full effect of this        medicine if they are also taking omeprazole. Separating the dose        of clopidogrel and omeprazole in time will not reduce this drug        interaction.    -   Other drugs that are expected to have a similar effect and        should be avoided in combination with clopidogrel include:        cimetidine, fluconazole, ketoconazole, voriconazole, etravirine,        felbamate, fluoxetine, fluvoxamine, and ticlopidine.”

Angiolillo et al. in Clin. Pharmacology & Therapeutics, pages 1-10 (Sep.15, 2010), report the results of a series of four metabolic DDI studiesusing omeprazole, pantoprazole and clopidogrel conducted in healthysubjects. Specifically, study 1 administered a 300-mg loading dose and75 mg/day maintenance dose of clopidogrel and omeprazole (80 mg)simultaneously to the healthy patients. Study 2 administered theclopidogrel and omeprazole of study 1 twelve (12) hours apart to thehealthy patients. In study 3, the amount of clopidogrel from study 1 wasincreased to 600-mg loading/150 mg/day maintenance dose. Study 4administered a 300-mg loading dose and 75 mg/day maintenance dose ofclopidogrel and pantoprazole (80 mg) simultaneously to the healthypatients. The results showed that a metabolic DDI was found to existbetween clopidogrel and omeprazole but not between clopidogrel andpantoprazole.

However, since not all PPIs inhibit CYP2C19 to the same extent, thepotential for a clinically relevant DDI with clopidogrel may not begeneralized to all PPIs. Thus, there is a need in the art for newmethods of treating patients suffering from heartburn who areconcomitantly being administered clopidogrel to treat a second diseasestate or to prevent of gastric bleeding or hemorrhage in patients beingtreated with clopidogrel.

SUMMARY OF THE PRESENT INVENTION

In one aspect, the present invention relates to a method of treatingheartburn and at least one second disease state in a patient in need oftreatment thereof. The method comprises the step of preferentiallytreating the patient with a therapeutically effective amount oflansoprazole, dexlansoprazole or combinations thereof to treat theheartburn, wherein the therapeutically effective amount of lansoprazole,dexlansoprazole or combinations thereof does not diminish theeffectiveness of the clopidogrel bisulfate that is being concomitantlyadministered to treat the at least one second disease state.

In the above method, the heartburn can be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD). Moreover, in theabove method, the at least one second disease state is acute coronarysyndrome, peripheral artery disease, myocardial infarction, stroke andcombinations thereof. In the above method, the patient is preferentiallytreated with a therapeutically effective amount of lansoprazole.Alternatively, in the above method, the patient is preferentiallytreated with a therapeutically effective amount of dexlansoprazole. Instill another alternative, in the above method, the patient ispreferentially treated with a therapeutically effective amount of acombination of lansoprazole and dexlansoprazole. In this method, thetherapeutically effective amount of lansoprazole can be between about 15mg and about 30 mg. In this method, the therapeutically effective amountof dexlansoprazole can be between about 30 mg and about 60 mg.Furthermore, in this method, the therapeutically effective amount oflansoprazole and dexlansoprazole can be between about 45 to about 90 mg.

In another aspect, the present invention relates to a method of treating(such as by healing) erosive esophagitis and at least one second diseasestate in a patient in need thereof. This method comprises the step ofpreferentially treating the patient with a therapeutically effectiveamount of lansoprazole, dexlansoprazole or combinations thereof to treatthe erosive esophagitis wherein the therapeutically effective amount oflansoprazole, dexlansoprazole or combinations thereof does not diminishthe effectiveness of the clopidogrel bisulfate that is beingconcomitantly administered to treat the at least one second diseasestate.

In the above method, the at least one second disease state is acutecoronary syndrome, peripheral artery disease, myocardial infarction,stroke and combinations thereof. In the above method, the patient ispreferentially treated with a therapeutically effective amount oflansoprazole. Alternatively, in the above method, the patient ispreferentially treated with a therapeutically effective amount ofdexlansoprazole. In still another alternative, in the above method, thepatient is preferentially treated with a therapeutically effectiveamount of a combination of lansoprazole and dexlansoprazole. In thismethod, the therapeutically effective amount of lansoprazole can bebetween about 15 mg and about 30 mg. In this method, the therapeuticallyeffective amount of dexlansoprazole can be between about 30 mg and about60 mg. Furthermore, in this method, the therapeutically effective amountof lansoprazole and dexlansoprazole can be between about 45 to about 90mg.

In yet another aspect, the present invention relates to a method ofpreventing gastric bleeding or hemorrhage associated with clopidogreltherapy. This method comprises the step of administering to a patientwho is concomitantly being administered or about to be administeredclopidogrel bisulfate, a therapeutically effective amount oflansoprazole, dexlansoprazole or combinations thereof, wherein thetherapeutically effective amount of lansoprazole, dexlansoprazole orcombinations thereof does not diminish the effectiveness of theclopidogrel bisulfate that is being concomitantly administered to saidpatient.

In this method, the clopidogrel bisulfate is being administered to thepatient to treat acute coronary syndrome, peripheral artery disease,myocardial infarction, stroke and combinations thereof. In the abovemethod, the patient is administered a therapeutically effective amountof lansoprazole. Alternatively, in the above method, the patient isadministered a therapeutically effective amount of dexlansoprazole. Instill another alternative, in the above method, the patient isadministered a therapeutically effective amount of a combination oflansoprazole and dexlansoprazole. In this method, the therapeuticallyeffective amount of lansoprazole can be between about 15 mg and about 30mg. In this method, the therapeutically effective amount ofdexlansoprazole can be between about 30 mg and about 60 mg. Furthermore,in this method, the therapeutically effective amount of lansoprazole anddexlansoprazole can be between about 45 to about 90 mg.

In still yet another aspect, the present invention relates to a methodof treating heartburn and at least one second disease state in a patientin need of treatment thereof. In this aspect, the method comprises thesteps of:

-   -   a) identifying a patient suffering from heartburn and at least        one second disease state, wherein said patient is being treated        with or about to be treated with clopidogrel bisulfate to treat        the at least one second disease state;    -   b) selecting from a class of proton pump inhibitors comprising        omeprazole, esomeprazole, lansoprazole, dexlansoprazole or        combinations thereof, at least one proton pump inhibitor to        administer to the patient, wherein administration of the proton        pump inhibitor to the patient does not diminish the        effectiveness of the clopidogrel bisulfate that is or will be        concomitantly administered to treat the at least one second        disease state, wherein the proton pump inhibitor selected is        dexlansoprazole, lansoprazole, or combinations thereof; and    -   c) administering to said patient a therapeutically effective        amount of dexlansoprazole, lansoprazole or combinations thereof        to treat the heartburn.

In the above method, the heartburn can be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD). Also, in the abovemethod, the at least one second disease state is acute coronarysyndrome, peripheral artery disease, myocardial infarction, stroke andcombinations thereof. In the above method, the patient is administered atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient is administered a therapeutically effectiveamount of dexlansoprazole. In still another alternative, in the abovemethod, the patient is administered a therapeutically effective amountof a combination of lansoprazole and dexlansoprazole. In this method,the therapeutically effective amount of lansoprazole can be betweenabout 15 mg and about 30 mg. In this method, the therapeuticallyeffective amount of dexlansoprazole can be between about 30 mg and about60 mg. Furthermore, in this method, the therapeutically effective amountof lansoprazole and dexlansoprazole can be between about 45 to about 90mg.

In still yet another aspect, the present invention relates to a methodof treating erosive esophagitis and at least one second disease state ina patient in need of treatment thereof. This method comprises the stepsof:

-   -   a) identifying a patient being treated for erosive esophagitis        and at least one second disease state, wherein said patient is        being treated with or about to be treated with clopidogrel        bisulfate to treat the at least one second disease state,    -   b) selecting from a class of proton pump inhibitors comprising        omeprazole, esomeprazole, lansoprazole, dexlansoprazole or        combinations thereof at least one proton pump inhibitor to        administer to the patient, wherein the administration of the        proton pump inhibitor to the patient does not diminish the        effectiveness of the clopidogrel bisulfate that is or will be        concomitantly administered to treat the at least one second        disease state, wherein the proton pump inhibitor selected is        dexlansoprazole, lansoprazole, or combinations thereof; and    -   c) administering to said patient a therapeutically effective        amount of dexlansoprazole, lansoprazole or combinations thereof        to treat the erosive esophagitis.

In the above method, the patient is administered a therapeuticallyeffective amount of lansoprazole. Alternatively, in the above method,the patient is administered a therapeutically effective amount ofdexlansoprazole. In still another alternative, in the above method, thepatient is administered a therapeutically effective amount of acombination of lansoprazole and dexlansoprazole. In this method, thetherapeutically effective amount of lansoprazole can be between about 15mg and about 30 mg. In this method, the therapeutically effective amountof dexlansoprazole can be between about 30 mg and about 60 mg.Furthermore, in this method, the therapeutically effective amount oflansoprazole and dexlansoprazole can be between about 45 to about 90 mg.

In still yet another aspect, the present invention relates topharmaceutical compositions comprising a proton pump inhibitor andclopidogrel bisulfate, wherein the proton pump inhibitor is selectedfrom the group consisting of: lansoprazole, dexlansoprazole andcombinations thereof. The pharmaceutical compositions of the presentinvention can be used for the treatment of at least one of the followingdiseases: heartburn, erosive esophagitis, acute coronary syndrome,peripheral artery disease, myocardial infarction, stroke andcombinations thereof. In the pharmaceutical compositions of the presentinvention, the proton pump inhibitor and clopidogrel bisulfate areadministered as a single dosage form. Alternatively, in thepharmaceutical compositions of the present invention, the proton pumpinhibitor and clopidogrel bisulfate are administered independently asseparate dosage forms.

In still yet a further aspect, the present invention relates to a methodof reducing the risk of an adverse drug interaction in a patientreceiving clopidogrel bisulfate. The method comprises the step of:

treating a patient who is concomitantly being administered atherapeutically effective amount of clopidogrel bisulfate with atherapeutically effective amount of lansoprazole, dexlansoprazole orcombinations thereof to treat heartburn, wherein the therapeuticallyeffective amount of lansoprazole, dexlansoprazole or combinationsthereof does not diminish the effectiveness of the clopidogrel bisulfateand further wherein said treatment reduces a risk of an adverse druginteraction between the clopidogrel bisulfate and the lansoprazole,dexlansoprazole or combinations thereof.

In the above method, the heartburn may be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD) or erosiveesophagitis. In the above method, the patient can be treated with atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of dexlansoprazole. Still further alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of a combination of lansoprazole and dexlansoprazole.In this method, the therapeutically effective amount of lansoprazole canbe between about 15 mg and about 30 mg. In this method, thetherapeutically effective amount of dexlansoprazole can be between about30 mg and about 60 mg. Furthermore, in this method, the therapeuticallyeffective amount of lansoprazole and dexlansoprazole can be betweenabout 45 to about 90 mg.

In still yet a further aspect, the present invention relates to a methodof treating heartburn in a patient receiving clopidogrel bisulfate. Themethod comprises the step of:

treating a patient who is concomitantly being administered atherapeutically effective amount of clopidogrel bisulfate with atherapeutically effective amount of lansoprazole, dexlansoprazole orcombinations thereof to treat a heartburn, wherein the therapeuticallyeffective amount of lansoprazole, dexlansoprazole or combinationsthereof does not diminish the effectiveness of the clopidogrel bisulfateand further wherein said treatment minimizes CYP2C19 interactionsbetween the clopidogrel bisulfate and the lansoprazole, dexlansoprazoleor combinations thereof. In this method, the therapeutically effectiveamount of lansoprazole can be between about 15 mg and about 30 mg. Inthis method, the therapeutically effective amount of dexlansoprazole canbe between about 30 mg and about 60 mg. Furthermore, in this method, thetherapeutically effective amount of lansoprazole and dexlansoprazole canbe between about 45 to about 90 mg.

In the above method, the heartburn may be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD) or erosiveesophagitis. In the above method, the patient can be treated with atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of dexlansoprazole. Still further alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of a combination of lansoprazole and dexlansoprazole.In this method, the therapeutically effective amount of lansoprazole canbe between about 15 mg and about 30 mg. In this method, thetherapeutically effective amount of dexlansoprazole can be between about30 mg and about 60 mg. Furthermore, in this method, the therapeuticallyeffective amount of lansoprazole and dexlansoprazole can be betweenabout 45 to about 90 mg.

In still yet a further aspect, the present invention relates to a methodof selecting a heartburn treatment for use in conjunction withconcomitant administration of clopidogrel bisulfate to a patient in needof treatment thereof. The method comprises the steps of:

identifying a heartburn treatment that minimizes CYP2C19 interactionsbetween the heartburn treatment and concomitant administration ofclopidogrel bisulfate to a patient in need of treatment thereof, whereinsaid heartburn treatment comprises a therapeutically effective amount oflansoprazole, dexlansoprazole or combinations thereof to treat theheartburn; and

selecting the heartburn treatment for use in conjunction withconcomitant administration of clopidogrel bisulfate to the patient.

In the above method, the heartburn may be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD) or erosiveesophagitis. In the above method, the patient can be treated with atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of dexlansoprazole. Still further alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of a combination of lansoprazole and dexlansoprazole.In this method, the therapeutically effective amount of lansoprazole canbe between about 15 mg and about 30 mg. In this method, thetherapeutically effective amount of dexlansoprazole can be between about30 mg and about 60 mg. Furthermore, in this method, the therapeuticallyeffective amount of lansoprazole and dexlansoprazole can be betweenabout 45 to about 90 mg.

In still yet another aspect, the present invention relates to a methodof treating heartburn in a patient who is also concomitantly receivingclopidogrel bisulfate. The method comprises the steps of:

identifying a heartburn treatment that minimizes CYP2C19 interactions ina patient receiving concomitantly the heartburn treatment andclopidogrel bisulfate;

selecting the heartburn treatment that minimizes CYP2C19 interactionsbetween the heartburn treatment and clopidogrel bisulfate in a patientwho is to be concomitantly treated with the heartburn treatment andclopidogrel bisulfate, wherein the heartburn treatment compriseslansoprazole, dexlansoprazole or combinations thereof; and

treating a patient being concomitantly administered clopidogrelbisulfate with a therapeutically effective amount of lansoprazole,dexlansoprazole or combinations thereof to treat the heartburn, whereinsaid lansoprazole, dexlansoprazole or combinations thereof minimizeCYP2C19 interactions with the clopidogrel bisulfate.

In the above method, the heartburn may be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD) or erosiveesophagitis. In the above method, the patient can be treated with atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of dexlansoprazole. Still further alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of a combination of lansoprazole and dexlansoprazole.In this method, the therapeutically effective amount of lansoprazole canbe between about 15 mg and about 30 mg. In this method, thetherapeutically effective amount of dexlansoprazole can be between about30 mg and about 60 mg. Furthermore, in this method, the therapeuticallyeffective amount of lansoprazole and dexlansoprazole can be betweenabout 45 to about 90 mg.

In still yet another aspect, the present invention relates to a methodof reducing undesirable CYP2C19 interactions between a heartburntreatment and concomitant administration of clopidogrel bisulfate in apatient in need of treatment thereof. The method comprises the step of:

administering a heartburn treatment to a patient in need of treatmentthereof, wherein the patient is concomitantly receiving clopidogrelbisulfate for treatment of at least one second disease state,

wherein the heartburn treatment comprises a therapeutically effectiveamount of lansoprazole, dexlansoprazole or combinations thereof to treatthe heartburn, and

further wherein the therapeutically effective amount of lansoprazole,dexlansoprazole or combinations thereof does not diminish theeffectiveness of the clopidogrel that is being concomitantlyadministered to treat the at least one second disease state and reducesundesirable CYP2C19 interactions between the lansoprazole,dexlansoprazole or combinations thereof and clopidogrel bisulfate.

In the above method, the heartburn may be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD) or erosiveesophagitis. In the above method, the patient can be treated with atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of dexlansoprazole. Still further alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of a combination of lansoprazole and dexlansoprazole.In this method, the therapeutically effective amount of lansoprazole canbe between about 15 mg and about 30 mg. In this method, thetherapeutically effective amount of dexlansoprazole can be between about30 mg and about 60 mg. Furthermore, in this method, the therapeuticallyeffective amount of lansoprazole and dexlansoprazole can be betweenabout 45 to about 90 mg.

In the above method, the at least one second disease state is acutecoronary syndrome, peripheral artery disease, myocardial infarction,stroke and combinations thereof.

In still yet another aspect, the present invention relates to a methodof treating heartburn in a patient concomitantly receiving clopidogrelbisulfate without causing significant CYP2C19 interactions between theheartburn treatment and clopidogrel bisulfate in the patient. The methodcomprises the step of:

administering a therapeutically effective amount of lansoprazole,dexlansoprazole or combinations thereof to a patient who isconcomitantly receiving clopidogrel bisulfate to treat heartburn,wherein the therapeutically effective amount of lansoprazole,dexlansoprazole or combinations thereof does not diminish theeffectiveness of the clopidogrel bisulfate and further wherein thelansoprazole, dexlansoprazole or combinations thereof do not causesignificant CYP2C19 interactions with the clopidogrel bisulfate.

In the above method, the heartburn may be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD) or erosiveesophagitis. In the above method, the patient can be treated with atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of dexlansoprazole. Still further alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of a combination of lansoprazole and dexlansoprazole.In this method, the therapeutically effective amount of lansoprazole canbe between about 15 mg and about 30 mg. In this method, thetherapeutically effective amount of dexlansoprazole can be between about30 mg and about 60 mg. Furthermore, in this method, the therapeuticallyeffective amount of lansoprazole and dexlansoprazole can be betweenabout 45 to about 90 mg.

In still yet another aspect, the present invention relates to a methodof using lansoprazole, dexlansoprazole or combinations thereof in apatient in need of treatment thereof. The method comprises the steps of

providing a patient that is concomitantly receiving clopidogrelbisulfate with a therapeutically effective amount of a heartburntreatment, wherein the heartburn treatment comprises a therapeuticallyeffective amount of lansoprazole, dexlansoprazole or combinationsthereof to treat the heartburn; and

informing the patient or a medical care worker that the lansoprazole,dexlansoprazole or combinations thereof may reduce CYP2C19 interactionsbetween the lansoprazole, dexlansoprazole or combinations andclopidogrel bisulfate.

In the above method, the heartburn may be associated with symptomaticnon-erosive gastroesophageal reflux disease (GERD) or erosiveesophagitis. In the above method, the patient can be treated with atherapeutically effective amount of lansoprazole. Alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of dexlansoprazole. Still further alternatively, in theabove method, the patient can be treated with a therapeuticallyeffective amount of a combination of lansoprazole and dexlansoprazole.In this method, the therapeutically effective amount of lansoprazole canbe between about 15 mg and about 30 mg. In this method, thetherapeutically effective amount of dexlansoprazole can be between about30 mg and about 60 mg. Furthermore, in this method, the therapeuticallyeffective amount of lansoprazole and dexlansoprazole can be betweenabout 45 to about 90 mg.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Section headings as used in this section and the entire invention hereinare not intended to be limiting.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. For therecitation of numeric ranges herein, each intervening number therebetween with the same degree of precision is explicitly contemplated.For example, for the range 6-9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated.

As used herein, the term “about” is used synonymously with the term“approximately.” Illustratively, the use of the term “about” indicatesthat values slightly outside the cited values, namely, plus or minus10%. Such dosages are thus encompassed by the scope of the claimsreciting the terms “about” and “approximately.”

As used herein, the term “active agent” refers to a proton pumpinhibitor, a clopidogrel metabolite (clopidogrel is a prodrug) orcombinations thereof.

The terms “administer”, “administering”, “administered” or“administration” refer to any manner of providing an active agent ordrug (such as, a PPI or a pharmaceutically acceptable salt thereof,clopidogrel, etc.) to a subject or patient. Routes of administration canbe accomplished through any means known by those skilled in the art.Such means include, but are not limited to, oral, buccal, intravenous,subcutaneous, intramuscular, transdermal, by inhalation and the like.

As used herein the term “clopidogrel” or the phrase “clopidogreltherapy” as used interchangeably herein, refers to clopidogrelbisulfate, which is sold under the brand name Plavix. The chemical namefor clopidogrel is methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). Clopidogrel is currently available as a 75mg or 300 mg tablet. Clopidogrel is typically used to treat patientssuffering from acute coronary syndrome, peripheral artery disease,myocardial infarction and combinations thereof.

As will be described in more detail herein, the methods of the currentinvention allow for clopidogrel to continue to be administered accordingto the manufacturer's suggested dosing of the compound. As used herein,the term “manufacturer's suggested dosing” signifies the dosingdisclosed in the package insert of the clopidogrel dosage form andavailable in a variety of pharmaceutical treatment references. Themethods of the current invention encompass the recommended dosing forall dosage forms, and include the treatment of all patients, for alldisease states in which clopidogrel treatment may be effective.

The term “dosage form” refers to any solid object, semi-solid, or liquidcomposition designed to contain a specific pre-determined amount (i.e.,dose) of a certain active agent. Suitable dosage forms may bepharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical ormucosal delivery or subcutaneous implants, or other implanted drugdelivery systems and the like. Preferably, the dosage forms describedherein may be considered to be solid, however, they may contain liquidor semi-solid components. More preferably, the dosage form is an orallyadministered system for delivering an active agent to thegastrointestinal tract of a subject. The dosage form of the presentinvention may exhibit modified release of the active agent.

By an “effective amount” or a “therapeutically effective amount” of anactive agent is meant a nontoxic but sufficient amount of the activeagent to provide the desired effect. The amount of active agent that is“effective” will vary from subject to subject, depending on the age andgeneral condition of the individual, the particular active agent oragents, and the like. Thus, it is not always possible to specify anexact “effective amount.” However, an appropriate “effective amount” inany individual case may be determined by one of ordinary skill in theart using routine experimentation.

By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable excipient,” or a “pharmaceuticallyacceptable additive,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects.

The phrase “proton pump inhibitor” or “PPI” refers to a compoundcomprising a substituted benzimidazole that suppress gastric acidsecretion by specific inhibition of the H⁺/K⁺ ATPase enzyme system ofthe secretory surface of the gastric parietal cell. Examples of PPIsinclude, lansoprazole, dexlansoprazole, omeprazole, esomeprazole,pantoprazole and salts thereof. Lansoprazole is described in U.S. Pat.No. 4,628,098, omeprazole is described in U.S. Pat. No. 4,255,431,esomeprazole is described in WO 92/08716 and pantoprazole is describedin U.S. Pat. No. 4,758,579. More specifically, lansoprazole is approvedfor the treatment of gastric acid-related diseases, specifically gastriculcers, duodenal ulcers, reflux esophagitis, and Zollinger-Ellisonsyndrome (ZES). Lansoprazole is supplied in delayed-release capsules fororal administration. The delayed-release capsules contain the activeingredient in the form of enteric-coated granules and are available in 2dosage strengths, 15 mg and 30 mg. Dexlansoprazole (the R-enantiomer oflansoprazole) delayed release capsule, also known as TAK-390MR anddexlansoprazole MR, (hereinafter referred to as dexlansoprazolecapsules) was approved for the indications of healing all grades oferosive esophagitis (EE), maintenance of healed EE and treatment ofheartburn associated with non-erosive gastroesophageal reflux disease.Dexlansoprazole capsules are supplied in 2 dosage strengths, 30 and 60mg, and each consists of 2 types of granules contained within a singlecapsule. Each type of granule has a different pH-dependent releaseprofile. The formulation has been designed to have approximately 25% ofthe drug released within 1 to 2 hours of administration, followed by asecond release phase within 4 to 5 hours for the remaining 75% of thedose. Omeprazole is currently supplied in delayed-release capsulescontaining 10 mg, 20 mg or 40 mg in the form of enteric-coated granules.Omeprazole has been approved for the indications of short-term treatmentof active duodenal ulcer, Helicobacter pylori eradication to reduce therisk of duodenal ulcer recurrence, gastroesophageal reflux disease(GERD), and maintenance of healing of EE. Esomeprazole is the S-isomerof omeprazole, a mixture of the S- and R-isomers. Esomeprazole issupplied in delayed-release capsules and in packets for adelayed-release oral suspension. Each delayed-release capsule contains20 mg or 40 mg of esomeprazole in the form of enteric-coated granules.Esomeprazole has been approved for the indications of GERD, riskreduction of nonsteroidal anti-inflammatory drug (NSAID)-associatedgastric ulcer, Helicobacter pylori eradication to reduce the risk ofduodenal ulcer recurrence, and ZES. Pantoprazole is supplied as adelayed-release oral suspension, available in one strength (40 mg), andas a delayed-release tablet, currently available in two strengths (20 mgand 40 mg). Pantoprazole is indicated in adults and pediatric patientsfive years of age and older for the short-term treatment (up to 8 weeks)in the healing and symptomatic relief of erosive esophagitis.Pantoprazole is indicated for maintenance of healing of erosiveesophagitis and reduction in relapse rates of daytime and nighttimeheartburn symptoms in adult patients with GERD. Also, pantoprazole isindicated for the long-term treatment of pathological hypersecretoryconditions, including ZES. Either crystalline forms or amorphous formsof the PPI can be used.

The term “subject” refers to an animal, preferably a mammal, including ahuman or non-human. The terms patient and subject may be usedinterchangeably herein.

The terms “treating” and “treatment” refer to reduction in severityand/or frequency of symptoms, elimination of symptoms and/or underlyingcause, prevention of the occurrence of symptoms and/or their underlyingcause, and improvement or remediation of damage. Thus, for example,“treating” a patient involves prevention of a particular disorder oradverse physiological event in a susceptible individual as well astreatment of a clinically symptomatic individual by inhibiting orcausing regression of a disorder or disease. The phrase “preferentiallytreating a patient” or “preferentially treating the patient” as usedherein refers to the reduction in severity and/or frequency of symptoms,elimination of symptoms and/or underlying cause, prevention of theoccurrence of symptoms and/or their underlying cause, and improvement orremediation of damage that is achieved by administering to the patientor subject one or more specific active agents or drugs of a certainclass over one or more active agents or drugs that are members of thesame class. For example, in the context of the present invention, asubject or patient who is concomitantly being administered or about tobe administered clopidogrel is preferentially treated with oradministered the PPIs lansoprazole, dexlansoprazole or combinationsthereof instead of using one or more of other PPIs such as omeprazole,esomeprazole, pantoprazole, etc. Lansoprazole, dexlansoprazole,omeprazole, esomeprazole and pantoprazole are all PPIs; however, in thecontext of the present invention, patients or subjects are preferablyadministered lansoprazole, dexlansoprazole or combinations thereof inlieu of omeprazole, esomeprazole, pantoprazole, etc. and anycombinations of omeprazole, esomeprazole, pantoprazole, etc.

II. The Present Invention

The present invention is based on the discovery that dexlansoprazole,lansoprazole and combinations thereof were found to be weak inhibitorsof CYP2C19. This finding led to the further discovery thatdexlansoprazole, lansoprazole and combinations thereof can beadministered concomitantly with clopidogrel to a subject in need oftreatment thereof without causing (1) a statistically significant changein the pharmacokinetics (AUC) in the active metabolite of clopidogrel;and (2) a statistically significant reduction in the inhibition ofplatelet aggregation (as a result of clopidogrel administration).Furthermore, subjects administered dexlansoprazole, lansoprazole andcombinations thereof concomitantly with clopidogrel are likely toexhibit a minimal or reduced risk of experiencing any adverse druginteraction between the clopiodgrel and the lansoprazole,dexlansoprazole or combinations thereof (thus reducing the likelihood orrisk to the patient that the treatment with lansoprazole,dexlansoprazole or combinations thereof would have to be stopped ordiscontinued). Moreover, because dexlansoprazole, lansoprazole andcombinations thereof were found to be weak inhibitors of CYP2C19,subjects administered dexlansoprazole, lansoprazole and combinationsthereof concomitantly with clopidogrel will experience minimized orreduced interactions between CYP2C19 and the dexlansoprazole,lansoprazole and combinations thereof and the clopidogrel. Again, suchminimized or reduced interactions between CYP2C19 and thedexlansoprazole, lansoprazole and combinations thereof and theclopidogrel reduce the likelihood or risk to the patient that treatmentwith lansoprazole, dexlansoprazole or combinations thereof would have tobe stopped or discontinued.

More specifically, the inventors of the present invention found thatwhen dexlansoprazole and lansoprazole were administered to subjectsconcomitantly receiving clopidogrel therapy, that the dexlansoprazole orlansoprazole did not exhibit a significant effect on (1) thepharmacokinetics of the active metabolite of clopidogrel; and (2) theinhibition of platelet aggregation, particularly when compared to thePPI's omeprazole and esomeprazole.

Thus, in one aspect, the present invention relates to a method oftreating heartburn in a patient in need of treatment thereof. Theheartburn to be treated in this aspect of the present invention can beassociated with symptomatic non-erosive gastroesophageal reflux disease(GERD), erosive esophagitis or combinations thereof. In this aspect, thepatient in need of treatment thereof is suffering from at least onesecond disease state for which the patient is concomitantly beingtreated with clopidogrel or about to be treated with clopidogrel(namely, treatment has not yet commenced). For example, said seconddisease state can be acute coronary syndrome, peripheral artery disease,myocardial infarction, stroke and combinations thereof. In addition, thepatient may also be suffering from a third or more disease states. Anexample of a third or more disease states may be any one or more ofhypertension, renal disease, cancer (such as colon cancer, breastcancer, prostate cancer, bladder cancer, liver cancer, pancreaticcancer, etc), diabetes, gout, dementia, Alzheimer's Disease, arthritis,etc.

In another aspect, the present invention relates to a method of treating(e.g. healing) erosive esophagitis in a patient. In this aspect, thehealing of the erosive esophagitis also includes or encompassescommencing the initial healing of erosive esophagitis as well asmaintaining any level of healing of erosive esophagitis that haspreviously been obtained or commenced in said patient for a certainpreexisting period of time (such as for one day, two days, three days,five days, one week, two weeks, three weeks, four weeks, two months,three months, four months, five months, six months, seven months, eightmonths, nine months, ten months, eleven months, twelve months, etc.).Also in this aspect, the patient in need of treatment thereof issuffering from at least one second disease state for which the patientis concomitantly being treated with clopidogrel or about to be treatedwith clopidogrel (namely, treatment has not yet commenced). For example,said second disease state can be acute coronary syndrome, peripheralartery disease, myocardial infarction, stroke and combinations thereof.In addition, the patient may also be suffering from a third or moredisease states. An example of a third or more disease states may be anyone or more of hypertension, renal disease, cancer (such as coloncancer, breast cancer, prostate cancer, bladder cancer, liver cancer,pancreatic cancer, etc), diabetes, gout, dementia, Alzheimer's Disease,arthritis, etc.

In another aspect, the present invention relates to methods ofpreventing (such as by reducing the risk) gastric bleeding or hemorrhagein a patient receiving clopidogrel therapy. This method involvesadministering (namely, preferentially treating) to a patient who isconcomitantly being administered or about to be administeredclopidogrel, a therapeutically effective amount of lansoprazole,dexlansoprazole or combinations thereof, wherein the therapeuticallyeffective amount of lansoprazole, dexlansoprazole or combinationsthereof does not diminish the effectiveness of the clopidogrel bisulfate(namely, the administration of the lansoprazole, dexlansoprazole orcombinations thereof does not cause (1) a statistically significantchange in the pharmacokinetics in the active metabolite of clopidogrel;and (2) a statistically significant reduction in the inhibition ofplatelet aggregation) that is being concomitantly administered to saidpatient. In this aspect of the present invention, the clopidogrel isbeing administered to the patient in order to treat acute coronarysyndrome, peripheral artery disease, myocardial infarction, stroke andany combinations thereof.

In still yet another aspect, the present invention relates to a methodof treating heartburn and at least one second disease state in a patientin need of treatment thereof. The heartburn to be treated can beheartburn associated with symptomatic non-erosive gastroesophagealreflux disease (GERD), erosive esophagitis or combinations thereof. Inthis aspect, the method involves first identifying a patient sufferingfrom heartburn and at least one second disease state, wherein saidpatient is being treated with or about to be treated with clopidogrelbisulfate to treat the at least one second disease state. After such apatient is identified, the next step of the method involves selectingfrom a class of proton pump inhibitors comprising at least the PPIsomeprazole, esomeprazole, lansoprazole, dexlansoprazole or combinationsthereof (the class can include other PPIs known in the art or laterdeveloped), at least one proton pump inhibitor to administer to thepatient, wherein administration of the proton pump inhibitor to thepatient does not diminish the effectiveness of the clopidogrel bisulfate(namely, the administration of the lansoprazole, dexlansoprazole orcombinations thereof does not cause (1) a statistically significantchange in the pharmacokinetics in the active metabolite of clopidogrel;and (2) a statistically significant reduction in the inhibition ofplatelet aggregation) that is or will be concomitantly administered totreat the at least one second disease state. Specifically, in thismethod, the proton pump inhibitor selected to be administered to thepatient is dexlansoprazole, lansoprazole, or combinations thereof. Thefinal step of the method involves administering to said patient atherapeutically effective amount of dexlansoprazole, lansoprazole orcombinations thereof to treat the heartburn. In this aspect of themethod, the second disease state can be acute coronary syndrome,peripheral artery disease, myocardial infarction, stroke andcombinations thereof. In addition, the patient may also be sufferingfrom a third or more disease states. An example of a third or moredisease states may be any one or more of hypertension, renal disease,cancer (such as colon cancer, breast cancer, prostate cancer, bladdercancer, liver cancer, pancreatic cancer, etc), diabetes, gout, dementia,Alzheimer's Disease, arthritis, etc.

In still yet another aspect, the present invention relates to a methodof treating (e.g. healing) erosive esophagitis and at least one seconddisease state, wherein said patient is being treated with or about to betreated with clopidogrel bisulfate to treat the at least one seconddisease state. After such a patient is identified, the next step of themethod involves selecting from a class of proton pump inhibitorscomprising at least the PPIs omeprazole, esomeprazole, lansoprazole,dexlansoprazole or combinations thereof (the class can include otherPPIs known in the art or later developed), at least one proton pumpinhibitor to administer to the patient, wherein administration of theproton pump inhibitor to the patient does not diminish the effectivenessof the clopidogrel bisulfate (namely, the administration of thelansoprazole, dexlansoprazole or combinations thereof does not cause (1)a statistically significant change in the pharmacokinetics in the activemetabolite of clopidogrel; and (2) a statistically significant reductionin the inhibition of platelet aggregation) that is or will beconcomitantly administered to treat the at least one second diseasestate. Specifically, in this method, the proton pump inhibitor selectedto be administered to the patient is dexlansoprazole, lansoprazole, orcombinations thereof. The final step of the method involvesadministering to said patient a therapeutically effective amount ofdexlansoprazole, lansoprazole or combinations thereof to treat theerosive esophagitis. In this aspect of the method, the second diseasestate can be acute coronary syndrome, peripheral artery disease,myocardial infarction, stroke and combinations thereof. In addition, thepatient may also be suffering from a third or more disease states. Anexample of a third or more disease states may be any one or more ofhypertension, renal disease, cancer (such as colon cancer, breastcancer, prostate cancer, bladder cancer, liver cancer, pancreaticcancer, etc), diabetes, gout, dementia, Alzheimer's Disease, arthritis,etc.

In still yet another aspect, the present invention relates to a methodof reducing the risk of an adverse drug interaction in a patientreceiving or about to receive treatment with clopidogrel to treat asecond disease state. For example, said second disease state can beacute coronary syndrome, peripheral artery disease, myocardialinfarction, stroke and combinations thereof. In addition, the patientmay also be suffering from third and more disease states. An example ofa third and more disease states may be any one or more of hypertension,renal disease, cancer (such as colon cancer, breast cancer, prostatecancer, bladder cancer, liver cancer, pancreatic cancer, etc), diabetes,gout, dementia, Alzheimer's Disease, arthritis, etc.

In still another aspect, the present invention relates to a method ofselecting a heartburn treatment for use in conjunction with concomitantadministration of clopidogrel to a patient in need of treatment thereof(such as to treat a second disease state, a third disease state, afourth disease state, etc. For example, said second disease state can beacute coronary syndrome, peripheral artery disease, myocardialinfarction, stroke and combinations thereof. In addition, the patientmay also be suffering from third and more disease states. An example ofa third and more disease states may be any one or more of hypertension,renal disease, cancer (such as colon cancer, breast cancer, prostatecancer, bladder cancer, liver cancer, pancreatic cancer, etc), diabetes,gout, dementia, Alzheimer's Disease, arthritis, etc.)). One step of thismethod involves identifying a heartburn treatment that minimizes orreduces CYP2C19 interactions between the heartburn treatment andconcomitant administration of clopidogrel to a patient in need oftreatment thereof. Preferably, the heartburn treatment comprises atherapeutically effective amount of lansoprazole, dexlansoprazole orcombinations thereof to treat the heartburn. Another step in the methodinvolves selecting a heartburn treatment for use in conjunction with theconcomitant administration of clopidogrel to the patient. In thisaspect, the patient may be receiving or be about to receive treatmentwith clopidogrel to treat a second disease state or subsequent diseasestates. After selecting such a heartburn treatment pursuant to the abovemethod, the patient receiving or about to receive treatment withclopidogrel can be treated with a therapeutically effective amount oflansoprazole, dexlansoprazole or combinations thereof to treat theheartburn, wherein said lansoprazole, dexlansoprazole or combinationsthereof minimize or reduce CYP2C19 interactions with the clopidogrel.

In still another aspect, the present invention relates to a method ofusing lansoprazole, dexlansoprazole or combinations thereof in a patientin need of treatment thereof. One step of the method involves providinga patient that is receiving or about to clopidogrel with atherapeutically effective amount of a heartburn treatment. Preferably,the heartburn treatment comprises a therapeutically effective amount oflansoprazole, dexlansoprazole or combinations thereof to treat theheartburn. Another step of the method involves informing the patient ora medical care worker that the lansoprazole, dexlansoprazole orcombinations thereof may reduce or minimize CYP2C19 interactions betweenthe lansoprazole, dexlansoprazole or combinations thereof andclopidogrel. This step of informing the patient or medical care worker(such as a doctor, nurse, physician's assistant, emergency medicaltechnician, etc.) that the lansoprazole, dexlansoprazole or combinationsthereof may reduce or minimize CYP2C19 interactions between thelansoprazole, dexlansoprazole or combinations thereof and clopidogreladvises or notifies the patient or medical care worker that the patientis likely to have a reduced risk of experiencing an adverse druginteraction (due to the fact that lansoprazole, dexlansoprazole andcombinations thereof were found to be weak inhibitors of CYP2C19)between the concomitant administration of the lansoprazole,dexlansoprazole or combinations thereof and clopidogrel.

As discussed previously herein, in the methods of the present invention,the patient is treated or preferentially treated with a therapeuticallyeffective amount of lansoprazole, dexlansoprazole or combinationsthereof wherein the therapeutically effective amount of lansoprazole,dexlansoprazole or combinations thereof does not diminish theeffectiveness of the clopidogrel (namely, the administration of thelansoprazole, dexlansoprazole or combinations thereof does not cause (1)a significant change in the pharmacokinetics in the active metabolite ofclopidogrel; and (2) a significant reduction in the inhibition ofplatelet aggregation) that is being concomitantly administered to treatthe at least one second disease state. Furthermore, a patient treatedpursuant to the methods of the present invention will exhibit a reducedrisk of experiencing an adverse drug interaction between the clopidogreland the lansoprazole, dexlansoprazole or combinations thereof (thelansoprazole, dexlansoprazole or combinations thereof comprising theheartburn treatment) such that treatment of the patient with thelansoprazole, dexlansoprazole or combinations thereof would not have tobe discontinued. Moreover, patients treated pursuant to the methods ofthe present invention will exhibit a reduction in undesirable CYP2C19interactions between the lansoprazole, dexlansoprazole or combinationsthereof and clopidogrel such that treatment of the patient with thelansoprazole, dexlansoprazole or combinations thereof would not have tobe stopped or discontinued.

The methods of the current invention as described herein allow forlansoprazole and dexlansoprazole to continue to be administeredaccording to the manufacturer's suggested dosing of the compound. Asused herein, the term “manufacturer's suggested dosing” signifies thedosing disclosed in the package insert of the lansoprazole anddexlansoprazole dosage forms and available in a variety ofpharmaceutical treatment references. The methods of the currentinvention encompass the recommended dosing for all dosage forms, andinclude the treatment of all patients for heartburn, in whichlansoprazole or dexlansoprazole may be effective. For example, 15 mg or30 mg lansoprazole may be administered to a patient one a day.Alternatively, 30 or 60 mg dexlansoprazole may be administered to apatient once a day.

In the methods of the present invention, the order is which thelansoprazole, dexlansoprazole (or combinations thereof) and clopidogrelare each administered is not critical. The lansoprazole ordexlansoprazole can be administered before or after the administrationof the clopidogrel and can also be administered at a period in timedifferent from when the clopidogrel is administered. Also, thelansoprazole, dexlansoprazole and clopidogrel can each be administeredas separate dosage forms or together in a single dosage form.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising a proton pump inhibitor and clopidogrelbisulfate, wherein the proton pump inhibitor is selected from the groupconsisting of: lansoprazole, dexlansoprazole and combinations thereof.The pharmaceutical compositions of the present invention can berespectively put to use by mixing the respective active components(namely, at least one proton pump inhibitor selected from lansoprazole,dexlansoprazole or combinations thereof and clopidogrel bisulfate)either all together or independently with a physiologically acceptablecarrier, excipient, binder, diluent, etc. and administering the mixtureor mixtures either orally or non-orally as a pharmaceutical composition.When the active components are formulated independently, the respectiveformulations can be extemporaneously admixed using a diluent or the likeand administered or can be administered independently of each other,either concurrently or at staggered times to the same subject.

The dosage form for said pharmaceutical composition includes such oraldosage forms as granules, powders, tablets, capsules, syrups, emulsions,suspensions, etc. and such non-oral dosage forms as injections (e.g.subcutaneous, intravenous, intramuscular and intraperitonealinjections), drip infusions, external application forms (e.g. nasalspray preparations, transdermal preparations, ointments, etc.), andsuppositories (e.g. rectal and vaginal suppositories).

These dosage forms can be manufactured by the per se known techniqueconventionally used in pharmaceutical procedures. For example, tomanufacture an oral dosage form, an excipient (e.g. lactose, sucrose,starch, mannitol, etc.), a disintegrator (e.g. calcium carbonate,carboxymethylcellulose calcium, etc.), a binder (e.g. α-starch, gumarabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, etc.), and a lubricant (e.g. talc, magnesiumstearate, polyethylene glycol 6000, etc.), for instance, are added tothe active component or components and the resulting composition iscompressed. Where necessary, the compressed product is coated, by theper se known technique, for masking the taste or for enteric dissolutionor sustained release. The coating material that can be used includes,for instance, ethylcellulose, hydroxymethylcellulose, polyoxyethyleneglycol, cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, and Eudragit™ (Rohm & Haas, Germany, methacrylic-acryliccopolymer).

Injections can be manufactured as follows. The active component orcomponents are dissolved, suspended or emulsified in an aqueous vehicle(e.g. distilled water, physiological saline, Ringer's solution, etc.) oran oily vehicle (e.g. vegetable oil such as olive oil, sesame oil,cottonseed oil, corn oil, etc. or propylene glycol) together with adispersant (e.g. Tween 80 (Atlas Powder, U.S.A.), HCO 60 (NikkoChemicals), polyethylene glycol, carboxymethylcellulose, sodiumalginate, etc.), a preservative (e.g. methyl p-hydroxybenzoate, propylp-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), anisotonizing agent (e.g. sodium chloride, glycerol, sorbitol, glucose,inverted sugar, etc.) and other additives. If desired, a solubilizer(e.g. sodium salicylate, sodium acetate, etc.), a stabilizer (e.g. humanserum albumin), a soothing agent (e.g. benzalkonium chloride, procainehydrochloride, etc.) and other additives can also be added.

A dosage form for external application can be manufactured by processingthe active component or components into a solid, semi-solid or liquidcomposition. To manufacture a solid composition, for instance, theactive component or components, either as they are or in admixture withan excipient (e.g. lactose, mannitol, starch, microcrystallinecellulose, sucrose, etc.), a thickener (e.g. natural gums, cellulosederivatives, acrylic polymers, etc.), etc., are processed into powders.The liquid composition can be manufactured in substantially the samemanner as the injections mentioned above. The semi-solid composition ispreferably provided in a hydrous or oily gel form or an ointment form.These compositions—may optionally contain a pH control agent (e.g.carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodiumhydroxide, etc.), and a preservative (e.g. p-hydroxybenzoic acid esters,chlorobutanol, benzalkonium chloride, etc.), among other additives.

Suppositories can be manufactured by processing the active component orcomponents into an oily or aqueous composition, whether solid,semi-solid or liquid. The oleaginous base that can be used includes, forinstance, higher fatty acid glycerides (e.g. cacao butter, Witepsols(Dynamit-Nobel), etc.), medium-chain fatty acids (e.g. Migriols(Dynamit-Nobel), etc.), vegetable oils (e.g. sesame oil, soybean oil,cotton-seed oil, etc.), etc. The water-soluble base includes, forinstance, polyethylene glycols, propylene glycol, etc. The hydrophilicbase includes, for instance, natural gums, cellulose derivatives, vinylpolymers, and acrylic polymers, etc.

The dosage of the pharmaceutical composition of the present inventionmay be appropriately determined with reference to the dosagesrecommended for the respective active components and can be selectedappropriately according to the recipient, the recipient's age and bodyweight, current clinical status, administration time, dosage form,method of administration, and combination of the active components,among other factors. For example, the dosage of the lansoprazole can be15 mg or 30 mg. The dosage of dexlansoprazole can be 30 mg and 60 mg.The dosage of clopidogrel bisulfate can be 75 mg. Such amounts can bereadily determined by those skilled in the art.

By way of example, and not of limitation, an example of the presentinvention shall now be given.

Example 1 A Phase 1, Randomized, Open-Label, 2-Period, Crossover DesignStudy to Assess the Effects of Multiple Oral Doses of Dexlansoprazole,Lansoprazole, Omeprazole or Esomeprazole on the Steady-StatePharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy SubjectsObjectives Primary:

The primary objective was to assess the potential for dexlansoprazole,lansoprazole, omeprazole or esomeprazole to affect the steady-statepharmacokinetics and pharmacodynamics of clopidogrel.

Secondary:

The secondary objective was to assess the safety of multiple doses ofclopidogrel in combination with dexlansoprazole, lansoprazole,omeprazole or esomeprazole in healthy subjects.

Methodology

This was a phase 1, randomized, open-label, single-center,multiple-dose, 2-period crossover study to assess the effects ofmultiple oral (PO) doses of dexlansoprazole, lansoprazole, omeprazole,or esomeprazole on the steady-state pharmacokinetics andpharmacodynamics of clopidogrel in healthy subjects who satisfied theselection criteria, were randomized equally into 8 regimen sequencegroups, 20 subjects each, according to the following proton pumpinhibitor (PPI) groups:

Regimen Sequence PPI Group Group N Period 1 Period 2 1 1 20 A B 2 20 B A2 3 20 A C 4 20 C A 3 5 20 A D 6 20 D A 4 7 20 A E 8 20 E A Regimen A:75 mg clopidogrel once daily (QD) for 9 Days. Regimen B: 75 mgclopidogrel + 30 mg lansoprazole QD for 9 days. Regimen C: 75 mgclopidogrel + 60 mg dexlansoprazole QD for 9 days. Regimen D: 75 mgclopidogrel + 80 mg (2 × 40 mg) omeprazole QD for 9 days. Regimen E: 75mg clopidogrel + 40 mg esomeprazole QD for 9 days.

Number of Subjects:

Planned: 160 subjectsSafety Set: 160 subjects; Pharmacokinetic Set: 158 subjects;Pharmacodynamic Set: 158 subjects

Diagnosis and Main Criteria for Inclusion:

Healthy subjects aged 18 to 55 years old, inclusive, who had a body massindex (BMI) between 18 and 30 kg/m² inclusive, and who were capable ofunderstanding and complying with protocol requirements. Subjects were ingood health as determined by the investigator (i.e., via medicalhistory, laboratory test results, electrocardiogram [ECG], vitals andphysical exam). Subjects signed a written, informed consent form priorto initiation of study procedures. The subject was a CYP2C19 extensivemetabolizer (wt/wt).

Test Product, Dose and Mode of Administration

Plavix (clopidogrel) 75 mg tablets, administered with one of thefollowing four PPIs:

-   -   Dexilant (dexlansoprazole) 60 mg capsules (30 count bottle),        Takeda Pharmaceuticals America, Inc./60 mg PO    -   Prevacid (lansoprazole) 30 mg capsules (100 count bottle),        Takeda Pharmaceuticals America, Inc./30 mg PO    -   Omeprazole 80 mg capsules (2×40 mg capsules), (30 count bottle),        Watson Pharmaceuticals, Inc./80 mg PO    -   Nexium (esomeprazole) 40 mg capsules (30 count bottle),        AstraZeneca./40 mg PO

Duration of Treatment:

There were 9 days of dosing in each of the 2 periods, which were 18 daysof dosing in total. There was a washout interval of 10 to 14 daysbetween the last dose of study drug in Period 1 and the first dose ofstudy drug in Period 2.

Clopidogrel 75 mg, QD, was given for 9 days in each of the two periods.Lansoprazole 30 mg, dexlansoprazole 60 mg, omeprazole 80 mg (2×40 mg),or esomeprazole 40 mg, QD, was given for 9 days in 1 of the 2 periods,depending on the randomization schedule.

Reference Therapy, Dose and Mode of Administration

Plavix (clopidogrel) 75 mg tablets (90 count bottle), Sanofi-Aventis/75mg PO administered alone.

Criteria for Evaluation: Pharmacokinetics:

On Day 9 of each period, blood samples were collected at predose and for24 hours postdose to measure plasma concentrations of clopidogrel andclopidogrel active and inactive metabolites. Pharmacokinetic parameterswere derived using non-compartmental analysis methods determined fromthe concentration-time data for all evaluable subjects. Actual samplingtimes were used in all computations involving sampling times. Thefollowing PK parameters were calculated: the peak plasma concentration(Cmax), time to reach the peak concentration (Tmax), area under theplasma concentration-time curve from time 0 to the time of lastquantifiable concentration (AUC(0-tlqc)), area under the plasmaconcentration-time curve from time 0 to tau over a dosing interval,where tau is the length of the dosing interval (AUC(0-tau)), apparentterminal elimination half life (T1/2), and the apparent terminalelimination rate constant (λz).

Pharmacodynamics:

Platelet function was assessed on Day-1, Days 7 to 9 prior to the doseof clopidogrel and 24-hours post Day 9 dose in each period. Thepharmacodynamic parameters activated by clopidogrel were determined from3 platelet function tests: Vasodilator-stimulated phosphoprotein (VASP),Aggregometry with adenosine diphosphate (ADP) and VerifyNow®. Plateletreactivity index (PRI), maximum platelet aggregation (MPA) with 5 and 20μM ADP, and P2Y12 platelet reactivity unit (PRU) were evaluated fromthese 3 tests, respectively.

Safety:

Safety variables included treatment-emergent adverse events (TEAEs),serious adverse events (SAEs), clinical laboratory testing (hematology,serum chemistry, and urinalysis), physical examination findings, vitalsign measurements, and 12-lead (ECG) results.

Statistical Methods:

For each PPI group, on Day 9 of each period, plasma concentrations ofclopidogrel, the active and inactive metabolites of clopidogrel andtheir pharmacokinetic parameters were tabulated and descriptivestatistics computed by regimens. To assess the effect of multiple dosesof the PPIs on the pharmacokinetics of clopidogrel and clopidogrel'sactive and inactive metabolite, analyses of variance (ANOVA) models withfactors of sequence, period, regimen and subjects within sequence wereused to compare these analytes: Tmax, kz, and the natural logarithm ofCmax, AUC(0-tlqc) and AUC(0-tau) values on Day 9 in the presence andabsence of a PPI. The ratio of clopidogrel with each PPI's central valueto that from the clopidogrel alone was determined for Cmax and AUC(s) byexponentiating the difference between the least square means oflogarithms. Additionally, for Cmax and AUC(s), 90% confidence intervals(CIs) for the ratio of regimen central values were determined byexponentiating the endpoints of 90% CIs for the difference oflogarithms. A conclusion of no effect of the PPIs on the PK ofclopidogrel and clopidogrel's active and inactive metabolite was reachedif the 90% CIs for the ratio of regimen central values for their Cmaxand AUC(s) were within the 0.80 to 1.25 interval.

For each PPI group, at 24 hrs post Day 9 dose of both periods,pharmacodynamic parameters from the platelet function tests weretabulated and descriptive statistics computed by regimens. ANOVA modelswith sequence, subject within sequence, period and regimen were fittedto the pharmacodynamic parameters. Pairwise comparison between regimenof clopidogrel with a PPI and clopidogrel alone was conducted within theframework of ANOVA. To assess the effect of multiple doses of 1 of the 4PPIs on the pharmacodynamics of clopidogrel, 90% CIs for the leastsquare mean difference between the 2 regimens for PRI were providedwithin the framework of ANOVA. A conclusion of no effect of each PPI onthe pharmacodynamics of clopidogrel was reached if the 90% CI for thedifference in the least square means of PRI was within the −15% to 15%interval.

For each PPI group, adverse events (AEs) that started or worsened inseverity after the first dose of study drug were summarized by regimens.Adverse events were classified according to the Medical Dictionary forRegulatory Activities (MedDRA) system organ class (SOC) and preferredterm (PT), and were tabulated with a breakdown by regimen within PPIgroup and by event severity. Similar AE tabulations were performed onthose events assessed by the investigator as related to study drug.Baseline, postdose, and change from baseline to postdose laboratoryvalues were summarized utilizing descriptive statistics for eachregimen. A table with predefined criteria for markedly abnormal valuesfor laboratory variables is presented. Individual subject data withmarkedly abnormal laboratory values are presented. Similarly, vitalsigns were summarized for each regimen in each PPI group by presentingdescriptive statistics for baseline, postdose, and change from baselineto postdose values. A table with predefined criteria for abnormalchanges from baseline for vital sign variables is presented. Individualsubject data with abnormal changes from baseline for vital signvariables is presented.

Summary of Results Subject Disposition:

A total of 160 subjects (mean [SD] age of 33.9 [7.26] years), including80 male and 80 female subjects, were randomized in the study from the552 unique subjects who were screened. One hundred and fifty subjectscompleted study drug. Two subjects in PPI Group 1, 4 subjects in PPIGroup 2, 2 subject in PPI Group 3 and 2 subjects in PPI Group 4prematurely discontinued study drug. The most common reasons forpremature discontinuation were major protocol violation and adverseevent. Each PPI group contained an equal number of men (N=20) and women(N=20). Subjects were predominantly White (98.1%). Overall mean (SD) BMIwas 26.1 (2.32) kg/m².

Pharmacokinetic Results:

Following administration of clopidogrel 75 mg concomitantly withdexlansoprazole 60 mg or lansoprazole 30 mg for 9 days, mean plasmaexposure (Cmax and AUCs) for clopidogrel active metabolite were slightlyless when compared to those values for clopidogrel alone. The decreasesin clopidogrel active metabolite plasma exposure were greater than withdexlansoprazole or lansoprazole when clopidogrel 75 mg was administeredwith omeprazole 80 mg or esomeprazole 40 mg for 9 days compared toclopidogrel alone. A summary of the PK parameter estimates ofclopidogrel active metabolite following clopidogrel 75 mg PO alone andafter multiple PO doses of dexlansoprazole 60 mg, lansoprazole 30 mg,omeprazole 80 mg, or esomeprazole 40 mg is presented below in Table 1:

TABLE 1 AUC (0-tlqc) AUC (0-tau) Tmax (a) (hr) Cmax (ng/mL) (ng hr/mL)(ng hr/mL) Lansoprazole PPI Group 1 - Clopidogrel Active MetaboliteClopidogrel Alone N 38 38 38 38 Mean 0.50 39.14 41.69 42.07 SD 0.50/1.5012.55 10.02 10.06 CV % NA 32 24 24 Clopidogrel with Lansoprazole 30 mg N38 38 38 38 Mean 0.50 30.01 36.42 36.71 SD 0.50/4.00 15.26 10.83 10.72CV % NA 51 30 29 Dexlansoprazole PPI Group 2 - Clopidogrel ActiveMetabolite Clopidogrel Alone N 36 36 36 36 Mean 0.50 38.85 41.25 41.52SD 0.50/1.50 15.70 14.69 14.67 CV % NA 40 36 35 Clopidogrel withDexlansoprazole 60 mg N 36 36 36 36 Mean 0.50 29.33 37.75 38.04 SD0.50/1.50 12.40 13.13 12.99 CV % NA 42 35 34 Omeprazole PPI Group 3 -Clopidogrel Active Metabolite Clopidogrel Alone N 38 38 38 38 Mean 0.5038.25 37.78 38.04 SD 0.50/1.00 12.46 12.04 12.08 CV % NA 33 32 32Clopidogrel with Omeprazole 80 mg N 38 38 38 38 Mean 0.50 22.55 26.2826.51 SD 0.50/3.00 10.68 8.80 8.84 CV % NA 47 33 33 Esomeprazole PPIGroup 4 - Clopidogrel Active Metabolite Clopidogrel Alone N 38 38 38 38Mean 0.50 40.98 42.35 42.62 SD 0.50/1.50 22.91 18.79 18.82 CV % NA 56 4444 Clopidogrel with Esomeprazole 40 mg N 38 38 38 38 Mean 0.50 24.6931.23 31.52 SD 0.50/1.50 10.64 9.94 9.89 CV % NA 43 32 31 NA = notapplicable.(a) Descriptive statistics for Tmax is median, minimum and maximum.

The 90% CIs for the ratio of the central values for the clopidogrelactive metabolite AUCs for clopidogrel with dexlansoprazole 60 mg orlansoprazole 30 mg compared with clopidogrel alone were within the 0.80to 1.25 no effect boundary. Coadministration of clopidogrel withdexlansoprazole 60 mg or lansoprazole 30 mg for 9 days resulted in anapproximately 30% decrease in clopidogrel active metabolite Cmax whencompared with clopidogrel alone. The 90% CIs for the ratio of thecentral value for the clopidogrel active metabolite Cmax whenclopidogrel was administered with dexlansoprazole 60 mg or lansoprazole30 mg were outside the 0.80 to 1.25 no effect boundary when comparedwith clopidogrel alone. Administration of clopidogrel with omeprazole 80mg or esomeprazole 40 mg resulted in a 16% to 44% decrease inclopidogrel active metabolite Cmax and AUCs when compared withclopidogrel alone. The 90% CI for the ratio of the central value for theclopidogrel active metabolite Cmax and AUCs when clopidogrel wasadministered with either omeprazole 80 mg or esomeprazole 40 mg extendedbelow the lower no effect boundary of 0.80 when compared withclopidogrel alone. A summary of the point estimates and 90% CIs for thePPI groups are presented in the following Table 2:

TABLE 2 Parameter Point Estimate 90% CI Lansoprazole PPI Group 1Clopidogrel Active Metabolite Cmax 0.7000 (0.6106-0.8026) AUC (0-tlqc)0.8573 (0.8020-0.9165) AUC (0-tau) 0.8578 (0.8039-0.9154)Dexlansoprazole PPI Group 2 Clopidogrel Active Metabolite Cmax 0.7340(0.6516-0.8269) AUC (0-tlqc) 0.9103 (0.8567-0.9672) AUC (0-tau) 0.9127(0.8597-0.9690) Omeprazole PPI Group 3 Clopidogrel Active MetaboliteCmax 0.5564 (0.4877-0.6347) AUC (0-tlqc) 0.6943 (0.6438-0.7487) AUC(0-tau) 0.6955 (06449-0.7499) Esomeprazole PPI Group 4 ClopidogrelActive Metabolite Cmax 0.6783 (0.5063-0.9087) AUC (0-tlqc) 0.8389(0.6440-1.0928) AUC (0-tau) 0.8359 (0.6503-1.0744)

Pharmacodynamic Results:

Following administration of clopidogrel alone for 9 days, the mean PRIwas approximately 41% to 48% across the four PPI groups. Followingadministration of clopidogrel with lansoprazole 30 mg or dexlansoprazole60 mg, the mean PRI increased 4.1% and 2.0% respectively, whileclopidogrel with omeprazole 80 mg and esomeprazole 40 mg resulted in themean PRI increasing by more than 11%. The results of ANOVA modelsapplied to PRI 24 hours post Day 9 dose of clopidogrel when administeredwith and without a PPI in subjects with complete data for both regimensare provided in the following Table 3:

TABLE 3 Difference in the LS-Means of PRI PPI Group (with PPI vs withoutPPI) 90% CI Lansoprazole 30 mg 4.1016 (0.0348, 8.1684)  Dexlansoprazole60 mg 2.0474 (−0.8555, 4.9503)  Omeprazole 80 mg 11.0407 (6.5219,15.5595) Esomeprazole 40 mg 11.4437 (7.1791, 15.7083)

For the lansoprazole 30 mg and dexlansoprazole 60 mg PPI groups, theupper bounds of 90% CIs for the difference in the LS-Means were lessthan 15%; therefore, the equivalence in PD was demonstrated betweenclopidogrel alone and clopidogrel with lansoprazole 30 mg ordexlansoprazole 60 mg regimen in terms of PRI. The lower bound of the90% CI for the omeprazole 80 mg group is much greater than 0; thereforethe effect of omeprazole 80 mg on clopidogrel PD was confirmed. Theeffect of esomeprazole 40 mg on clopidogrel PD was very similar toomeprazole 80 mg, as the upper bound of the 90% CI extended above the15% boundary.

Following administration of clopidogrel with dexlansoprazole 60 mg, thedifference when compared with clopidogrel alone in either MPA was notstatistically significant (p-value>0.05). When clopidogrel wasadministered with lansoprazole 30 mg, the differences when compared withclopidogrel alone in MPA were similar to dexlansoprazole 60 mg butstatistically significant. For both dexlansoprazole 60 mg andlansoprazole 30 mg, the mean differences were not more than 5%. Comparedwith clopidogrel alone, clopidogrel with omeprazole 80 mg or withesomeprazole 40 mg increased MPA with both 5 μM and 20 μM by 8 to 10%and these effects were statistically significant. The results of theanalyses of MPA at 24 hours post Day 9 dose for subjects with completedata in each PPI group are provided in the following Table 4:

TABLE 4 Clopidogrel Alone Clopidogrel + PPI PPI Group Mean (SD) Mean(SD) P-Values MPA with 5 μM ADP (%) at 24 Hours Post Day 9 DoseLansoprazole 30 mg 28.1 (6.76)  30.8 (9.35)  0.035* Dexlansoprazole 60mg 34.6 (14.23) 36.2 (16.87) 0.445 Omeprazole 80 mg 34.2 (12.32) 42.5(14.74) <0.001*** Esomeprazole 40 mg 29.3 (10.41) 38.2 (17.77) <0.001***MPA with 20 μM ADP (%) at 24 Hours Post Day 9 Dose Lansoprazole 30 mg36.7 (9.11)  41.6 (12.65) 0.004** Dexlansoprazole 60 mg 43.1 (13.24)46.3 (16.93) 0.148 Omeprazole 80 mg 43.5 (14.00) 53.5 (13.75) <0.001***Esomeprazole 40 mg 39.3 (13.22) 47.9 (15.77) <0.001*** *,**,***p-value <0.05, 0.01 and 0.001, respectively.

Compared with clopidogrel alone, the increases in PRU when clopidogrelwas coadministered with either dexlansoprazole 60 mg, lansoprazole 30mg, omeprazole 80 mg, or esomeprazole 40 mg were statisticallysignificant; however, these changes were greatest for omeprazole 80 mgand esomeprazole 40 mg (>50 units increase) compared withdexlansoprazole 60 mg and lansoprazole 30 mg (<20 units increase). Theresults of the analyses of the PRU at 24 hours postdose on Day 9 insubjects with complete data for both regimens are provided in thefollowing Table 5:

TABLE 5 Clopidogrel Alone Clopidogrel + PPI PPI Group Mean (SD) Mean(SD) P-Values PRU (%) at 24 Hours Post Day 9 Dose Lansoprazole 30 mg114.9 (56.44) 131.8 (71.27) <0.001*** Dexlansoprazole 60 mg 124.2(79.10) 146.7 (84.45) 0.024** Omeprazole 80 mg 133.0 (67.62) 201.5(59.65) <0.001*** Esomeprazole 40 mg 121.1 (50.64) 177.6 (55.37)<0.001*** *,**,***p-value < 0.05, 0.01 and 0.001, respectively.

Safety Results:

Overall, 103 (64%) of 160 subject experienced 1 or more TEAEs. Thenumber of subjects with treatment-related AEs were 81 (51%) of 160subjects. All TEAEs were mild or moderate in severity.

In all PPI groups, regardless of regimen, the most common AEs wereheadaches and gastrointestinal disorders, which included nausea andabdominal pain. Events of ecchymosis, which is a characteristic ofclopidogrel exposure, were reported in nearly all regimens and most wereconsidered to be related to study drug.

One subject experienced an SAE of serum sickness-like reaction that wasconsidered to be related to study drug. Three subjects experienced TEAEsthat lead to premature discontinuation from the study. During physicalexamination, one subject reported neurological changes from Baselinedescribed as generalized and symmetrical weakness in both legs andfatigue, with slow voluntary movements and rate of speech. These wereconsidered to be AEs and the subject was prematurely discontinued.Elevated pulse rates were observed in several subjects; however, thesesubjects with sporadic increases in pulse rates had normal bloodpressure and rates of respiration as well as ECG readings at the timeswhen their pulse rates were higher than normal. No clinically meaningfulchanges from baseline or markedly abnormal values were observed for anychemistry or hematology values or ECG character values.

CONCLUSIONS

This study confirmed that the positive control, omeprazole 80 mg,significantly affected the pharmacokinetics of clopidogrel activemetabolite and reduced clopidogrel's inhibition of platelet aggregation.The effect of esomeprazole 40 mg on the pharmacokinetics of clopidogrelactive metabolite and inhibition of platelet aggregation was alsosignificant to a similar degree as that of omeprazole 80 mg. Incontrast, the effect of dexlansoprazole 60 mg or lansoprazole 30 mg onthe pharmacokinetics of clopidogrel active metabolite and clopidogrel'sinhibition of platelet aggregation was not significant and/or less thanthose of omeprazole 80 mg or esomeprazole 40 mg. These results suggestthat the potential effects of PPIs on clopidogrel's activity could beminimized by use of dexlansoprazole or lansoprazole (weak CYP2C19inhibitors) rather than esomeprazole or omeprazole (potent CYP2C19inhibitors).

What is claimed is:
 1. A method of treating heartburn or erosiveesophagitis and at least one second disease state in a patient in needof treatment thereof, the method comprising the step of: a) identifyinga patient suffering from heartburn or erosive esophagitis and at leastone second disease state, wherein said patient is being treated with orabout to be treated with clopidogrel to treat the at least one seconddisease state; b) preferentially selecting dexlansoprazole from a groupof proton pump inhibitors to administer to the patient; and c)administering to said patient a therapeutically effective amount ofdexlansoprazole to treat the heartburn or erosive esophagitis.
 2. Themethod of claim 1, wherein the heart burn is heartburn associated withsymptomatic non-erosive gastroesophageal reflux disease.
 3. The methodof claim 1, wherein the administration of the dexlansoprazole to thepatient does not inhibit CYP2C19 interactions between thedexlansoprazole and clopidogrel.
 4. The method of claim 1, wherein thepharmacological activity of the clopidogrel that is administered is toconcomitantly treat the at least one second disease state.
 5. The methodof claim 1, wherein the at least one second disease state is acutecoronary syndrome, peripheral artery disease, myocardial infarction,stroke and combinations thereof.
 6. A method of treating heartburn orerosive esophagitis in a patient concomitantly receiving clopidogrelwithout inhibiting CYP2C19 interactions between the heartburn oresophagitis treatment and clopidogrel in the patient, the methodcomprising the step of: preferentially administering a therapeuticallyeffective amount of dexlansoprazole to a patient who is concomitantlyreceiving clopidogrel to treat heartburn or erosive esophagitis, whereinthe therapeutically effective amount of dexlansoprazole does not (i)inhibit the pharmacological activity of the clopidogrel; and (ii)inhibit CYP2C19 interactions between the dexlansoprazole and theclopidogrel.
 7. The method of claim 6, wherein the heartburn isheartburn associated with symptomatic non-erosive gastroesophagealreflux disease.
 8. The method of claim 6, wherein the at least onesecond disease state is acute coronary syndrome, peripheral arterydisease, myocardial infarction, stroke and combinations thereof.
 9. Amethod for maintaining the pharmacokinetics of clopidogrel when treatingheartburn or erosive esophagitis using dexlansoprazole in a patient thatis in need of treatment and is also being treated for at least onesecond disease state, the method comprising the steps of: preferentiallyadministering a therapeutically effective amount of dexlansoprazole totreat heartburn or erosive esophagitis in a patient who is concomitantlyreceiving or about to receive a therapeutically effective amount ofclopidogrel for treatment of at least one second disease state, whereinthe therapeutically effective amount of dexlansoprazole does not cause astatistically significant change in the pharmacokinetics of theclopidrogel.
 10. The method of claim 9, wherein the heartburn isheartburn associated with symptomatic non-erosive gastroesophagealreflux disease.
 11. The method of claim 9, wherein the at least onesecond disease state is acute coronary syndrome, peripheral arterydisease, myocardial infarction, stroke and combinations thereof.
 12. Themethod of claim 9, wherein the administration of the dexlansoprazole tothe patient does not inhibit CYP2C19 interactions between thedexlansoprazole and clopidogrel.